Genetic approaches to probe spatial coding in the medial entorhinal cortex

Abstract

The medial entorhinal cortex is a key component of the brain’s spatial navigation and memory system. It is the site where grid cells were discovered, i.e. neurons that are active at several locations in an environment, thus giving rise to a hexagonal ’grid’-like firing pattern. Experimental evidence suggests that inputs from the hippocampus, medial septum, and other brain regions, together with specific local connectivity are factors that contribute to the emergence of the grid cell pattern. To date, it is not clear how the hippocampus, which is also involved in spatial behaviors and projects to the MEC, contributes to grid cell function. I addressed this question by recording grid cells in mice with impaired hippocampal function. My results suggest that impaired spatial hippocampal coding does not disrupt grid cell firing. Furthermore, I gathered evidence that the MEC, as opposed to the hippocampus, is required for path integration. To probe how specific MEC neurons support spatial behavior, we need tools to manipulate them selectively. To this end, molecular markers must be identified and assigned to functional cell types. Two promising candidates are reelin (RE) and calbindin (CB). These proteins are expressed in anatomically distinct cell types. While in vitro these neurons are distinct with respect to their electrophysio- logical properties, it is still unclear how these differences correlate to in vivo firing patterns. I addressed this question by using two mouse lines to optogenetically tag RE + and CB + neurons. I find no major difference between the two populations, except for the pattern of projections to other brain regions. Also, I reveal the existence of a previously unknown projection from the parasubiculum to the contralateral MEC, that, along with pyramidal CB + neuron projections, appear to inhibit the contralateral MEC. These results suggest that the firing patterns of RE + and CB + cells are surprisingly similar, and that these markers may be valuable tools for studying components of cross-hemispheric connections.